Summary of work: The neuroanatomic and neurophysiologic underpinnings of age- associated cognitive and memory change remain unclear, as there are few studies of longitudinal brain changesin individuals without dementia. We are performing annual magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change. These evaluations will allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease (AD). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including genetic risk factors and the effects of sex steroid and other hormones. We are performing studies of the effects of estrogen and androgenic hormones on cognition and the brain in older women and men, respectively. Through the Women's Health Initiative Study of Cognitive Aging (WHISCA), we are also performing an ancillary study of specific cognitive abilities and affect in the large randomized trial of hormone therapy in the Women's Health Initiative. We continued the development and validation of new tools for processing images for longitudinal studies. We validated our approach for analysis of structural MRI data and developed an approach for parcellation of the brain into volumes of interest that can be applied to large imaging databases. We published a report delineating longitudinal age-changes over four years in gray and white matter, as well as cerebrospinal volumes, in older individuals without dementia. We demonstrated longitudinal tissue loss even in very healthy elderly and found that the rate of tissue loss was greater in individuals who had some health problems. Our longitudinal analysis of gray matter revealed a regional pattern of tissue loss, whereas white matter changes were more widespread. Our emphasis over the last year has been on the processing of additional followup MRI and PET data, emphasizing the analysis of the PET data while the next wave of MRI follow-ups are performed. The PET findings indicate cross-sectional and longitudinal effects of age, with decreased blood flow in specific regions in older compared with younger individuals. Our findings have guided our development of specific probes for examination of cognitive and brain changes in the elderly. We have performed and published studies of age differences in spatial navigation using computer-based virtual environments and have completed a study of 52 individuals, using functional magnetic resonance imaging to examine the neural basis of age differences in spatial navigation. In addition, we published a study investigating age differences in prefrontal functioning, showing differential effects of age on orbital frontal and dorsolateral prefrontal functions. We also completed and published a functional magnetic resonance imaging study of age differences in orbital frontal aging using tasks that differentially activate mesial versus lateral orbital frontal functioning. These findings showed the expected frontal activations in the young but not older subjects and indicated compensatory activations in more posterior regions in older individuals. Our studies of hormones as modulators of cognitive and brain aging also continue. We demonstrated positive associations between an index of free testosterone and memory and attentional functions in older men. Moreover, we reported that higher free (but not total) testosterone was associated with a reduced risk for Alzheimer's Disease. Through the WHISCA study, we investigated the effects of combination estrogen pllus progestin (E + P) treatment versus placebo on cognition and affect in older postmenopausal women in the E + P arm of the WHI hormone treatment trials. We have examined 1416 women with up to 3 annual assessments prior to termination of study medications in the combination E + P arm of the main WHI trial due to an adverse risk profile. Data analysis is underway for the estrogen only arm of the WHI trials, as study medications were terminated early this year. Cognitive assessments of WHISCA volunteers are continuing and will provide information on the effects of discontinuation of treatment. These studies will contribute to our understanding of the effects of steroid hormones on age-related cognitive changes in the elderly.